有机化学人才网 | 最新人才 | 最新职位 | 技术交易 | 药物合成 |
   
全站搜索: |
  您当前位置:网站首页 >> 药物合成路线图解
 

药物详细合成路线

Name Mivobulin isethionate;NSC-635370 [(1:1) salt];NSC-370147(racemic hydrate);NSC-350386(racemic HCl hydrate);NSC-613863 [(+)-(R)-isomer];CI-980;NSC-613862(free base)
Chemical Name (-)-(S)-N-(5-Amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-yl)carbamic acid ethyl ester 2-hydroxyethylsulfonate
CAS 126268-81-3
Related CAS 122332-18-7 (free base)
Formula C19H25N5O6S
Structure
Formula Weight 451.505
Stage I/II 期临床
Company Pfizer (Originator), National Cancer Institute (Codevelopment)
Activity/Mechanism Brain Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Oncolytic Drugs, Antimitotic Drugs, Microtubule-Stabilizing Agents
Syn. Route 3
Route 1
synthesis of ci-980:the condensation of n-(2-amino-4-chloro-3-nitropyridin-6-yl)carbamic acid ethyl ester (i) with (1r,2s)-2-amino-1-phenyl-1-propanol (ii) by means of triethylamine in refluxing ethanol gives (1s,2r)-n-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (iii), which is oxidized with cro3-pyridine in dichloromethane yielding the corresponding ketone (iv). the reductocyclization of (iv) with h2 over rani in glacial acetic acid affords the free base of title compound (v), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.
List of intermediates No.
ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate (i)
1-azabicyclo[3.2.1]octan-6-one (ii)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate (iii)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate (iv)
2-(1-azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt (v)
6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vi)
Reference 1:
    graul, a.; martell, a.m.; castaner, j.; mivobulin isethionate. drugs fut 1997, 22, 9, 980.
Reference 2:
    carroll, t.g. jr. (southern research institute); (2s)-(5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido[3,4-b]pyrazin-7-yl)-carbamic acid, ethyl ester. ep 0336345; jp 1989305087; us 4866059 .

Route 2
synthesis of [14c]-labeled ci-980:the reaction of n-(ethoxycarbonyl)-l-alanine (vii) with n-methoxy-n-methylamine (viii) by means of carbonyldiimidazole (cdi) in thf/dichloromethane gives the corresponding amide (ix), which is treated with phenylmagnesium bromide (1 mol) yielding the bromomagnesium salt (x). the bromination of [14c]-labeled benzene (xi) with br2/hbr/h2o2 gives the labeled bromobenzene (xii), which is converted into the corresponding grignard reagent (xiii) by reaction with mg and dibromoethane in ether. the reaction of the previously obtained magnesium salt of alaninamide (x) with the labeled grignard reagent (xiii) affords the labeled carbamate (xiv), which is reduced with nabh4 in methanol and treated with koh giving a mixture of the oxazolidinone (xv) and the aminoalcohol (xvi), separated by acidic extraction. the hydrolysis of the oxazolidinone (xv) with koh yielded the desired aminoalcohol (xvi). the aminoalcohol (xvi) by means of triethylamine in refluxing ethanol gives (1s,2r)-n-[2-amino-4-(2-hydroxy-1-methyl-2-phenylethylamino)-3-nitropyridin-6-yl]carbamic acid ethyl ester (xvii), which is oxidized with cro3-pyridine in dichloromethane yielding the corresponding ketone (xviii). the reductocyclization of (xviii) with h2 over rani in glacial acetic acid affords the free base of title compound (xix), which is finally treated with 2-hydroxyethanesulfonic acid in methanol.
List of intermediates No.
1-azabicyclo[3.2.1]octan-6-one (xvi)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate (xvii)
ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate (xviii)
2-(1-azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt (ix)
6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vi)
(5r,6r)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vii)
ethyl 2-anilinoacetate (viii)
ethyl 2-(1-phenylhydrazino)acetate (ix)
ethyl 2-[(1s,2s,13s,21r)-22-(cyclopropylmethyl)-2,16-dihydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate (x)
ethyl 2-[(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate (xi)
(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-hydroxyethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol (xii)
(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-11-(2-fluoroethyl)-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-2-ol (xiv)
(1s,2r)-n,n-diethyl-2-formyl-1-phenylcyclopropanecarboxamide (xv)
2-chloro-1-[4-(2,3,4-trimethoxybenzyl)-1-piperazinyl]-1-ethanone (xiii)
5-bromo-2,2-difluoro-1,3-benzodioxole (xi)
(xii)
(xiii)
(xiv)
(xv)
(4as,6r,7r,8s,8as)-6-({(2r,3s,4r,5r,6s)-5-(benzyloxy)-2-[(benzyloxy)methyl]-4,6-dimethoxytetrahydro-2h-pyran-3-yl}oxy)-8-methoxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl benzoate (xvi)
Reference 1:
    graul, a.; martell, a.m.; castaner, j.; mivobulin isethionate. drugs fut 1997, 22, 9, 980.
Reference 2:
    woo, p.w.k.; lee, h.t.; synthesis of [14c]ci-980, ethyl [5-amino-1,2-dihydro-2(s)-methyl-3-[14c]phenylpyrido[3,4-b]pyrazin-7 -yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. j label compd radiopharm 1994, 34, 1, 1-10.

Route 3
3) synthesis of [3h]-labeled ci-980:the reaction of butyllithium with m-dibromobenene (xvii) in ether gives the monolithium derivative (xviii), which is condensed with n-(ethoxycarbonyl)-l-alanine (vii) yielding the carbamate (xix). the reduction of (xix) with nabh4 in methanol affords the hydroxylated carbamate (xx), which is treated with naoh in methanol to give the aminoalcohol (xxi). the condensation of n-(2-amino-4-chloro-3-nitropyridin-6-yl)carbamic acid ethyl ester (i) with 2(s)-amino-1-(3-bromophenyl)-1-propanol (xxi) by means of triethylamine in refluxing ethanol gives n-[2-amino-4-[2-(3-bromophenyl)-2-hydroxy-1(s)-methylethylamino]-3-nitropyridin-6-yl]carbamic acid ethyl ester (xxii), which is oxidized with cro3-pyridine in dichloromethane yielding the corresponding ketone (xxiii). the reductocyclization of (xxiii) with fe and acetic acid affords the 3-bromo analogue of ci-980 (xxiv), which is finally hydrogenated with 3h2 over pd/c in thf, and treated with 2-hydroxyethanesulfonic acid in methanol.
List of intermediates No.
ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate (i)
6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vi)
(5r,6r)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane (vii)
(1s,2r)-n,n-diethyl-2-[(1r)-1-hydroxy-3-(trimethylsilyl)-2-propynyl]-1-phenylcyclopropanecarboxamide (xvii)
(1s,2r)-2-[(1r)-1-azido-3-(trimethylsilyl)-2-propynyl]-n,n-diethyl-1-phenylcyclopropanecarboxamide (xviii)
(4s)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one (xix)
octanal (xx)
(4s)-4-benzyl-3-[(2s,3r)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one (xxi)
(4s)-4-benzyl-3-((2s,3r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoyl)-1,3-oxazolidin-2-one (xxii)
(2s,3r)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoic acid (xxiii)
2,4,6-trichlorobenzoyl chloride (xxiv)
Reference 1:
    graul, a.; martell, a.m.; castaner, j.; mivobulin isethionate. drugs fut 1997, 22, 9, 980.
Reference 2:
    lee, h.t.; woo, p.w.k.; synthesis of [3h]ci-980, ethyl[5-amino-1,2-dihydro-2(s)-methyl-3(3-[3h]phenyl)pyrido[3,4-b] pyrazin-7-yl]carbamate isethionate salt, a tubulin-binding, antimitotic, broad-spectrum antitumor agent. j label compd radiopharm 1994, 34, 1, 11-16.

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名(-)-(S)-N-(5-氨基-2-甲基-3-苯基-l,2-二氢吡啶并[3,4-b]吡嗪-7-基)氨;英文名Mivobulin isethionate;NSC-635370 [(1:1) salt];NSC-370147(racemic hydrate);NSC-350386(racemic HCl hydrate);NSC-613863 [(+)-(R)-isomer];CI-980;NSC-613862(free base);CAS[126268-81-3]

 
推荐VIP企业
无锡景耀生物科技有限公司
杭州卢普生物科技有限公司
宁波赛伦化工有限公司
苏州昊赛生物科技有限公司
北京嘉盛扬医药科技有限公司
上海泽涵生物医药科技有限公司
河北固安三利化工公司
郑州凯普瑞生物技术有限公司
上海药谷药业有限公司
兰州康寓信生物科技有限公司
湖北朗昕生化药业有限公司
武汉福鑫化工有限公司
嘉兴市英南化工有限公司
苏州迪飞医药科技有限公司
北京富安凯科技有限公司
上海盛中医药化工有限公司
连云港天和化学有限公司
南京晨瑞医药科技有限公司
南京苏如化工有限公司
常州瑞盛化工有限公司
热门文章
FDA 批准首个产后抑郁症治疗
丁香播报:布洛芬和对乙酰氨基酚
《β受体阻滞剂在高血压应用中的
受响水爆炸影响,原药市场供需矛
江苏一化工企业发生爆炸,曾被列
拜耳的19.5亿欧元究竟花在了
FDA 批准罗氏肿瘤免疫疗法
带你认识第一款专门治疗产后抑郁
润丰股份致力于打造欧盟农化品活
欧盟批准罗氏血友病药物 Hem
山东地区醋酸价格
华北地区丁二烯市场报盘走高
陕西地区醋酸价格
华北地区醋酸价格
华东地区BDO市场弱势整理
华东地区邻苯市场行情维稳
山东地区二氯甲烷市场价格上调
华东地区BDO市场商谈整理
河北地区醋酸价格
河北地区醋酸价格
 友情链接
有机化学人才网  
首页 | 广告服务 | 建站服务 | 关于我们 | 联系我们 | 版权声明